Reward is an operational concept used to describe the positive value that an animal attributes to an object, behavior, or internal physical state. The recently development of optogentics, a method that allows for targeted activation of neurons with light (Britt, J. P. & Bonci, A. Optogenetic interrogations of the neural circuits underlying addiction. Current opinion in neurobiology, (2013); Nieh, E. H., Kim, Namburi, P. & Tye, K. M. Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors. Brain research (2012); and Saunders, B. T. & Richard, J. M. Shedding light on the role of ventral tegmental area dopamine in reward. The Journal of neuroscience: the official journal of the Society for Neuroscience 31, 18195-18197, (2011)), has led to significant advancements in the understanding of the reward system, by enabling dissection of the specific neurons involved in the circuitry, their projections, inputs and specific activation patterns. The reward circuitry is comprised of striatal, limbic, and pre-frontal cortical structures, in which midbrain dopamine (DA) neurons play a critical modulatory role. The VTA receives inputs from the lateral dorsal tegmentum (LDTg), lateral habenula (LHb), lateral hypothalamus (LH) and from the amygdala (Amy). It projects to the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC) and the amygdala. Additional direct and indirect pathways also exist, connecting the various structures comprising the reward system. The specific circuit mediating a defined signal determines the behavioral outcome, as exemplified by the activity of the dopamine neurons in the VTA, which can either induce preference or aversion, depending on the source of the input signal (Lammel, S., Lim, B. K., Ran, C., Huang, K. W. Malenka, R. C. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212-217, (2012)) and the projections that transmit the signal. Deciphering the specific circuits that mediate the effects of the reward system on the immune response is therefore essential to enable manipulations for therapuetic purposes.
While there is significant data suggesting that dopamine directly affects immune cells (Brito-Melo, G., Nicolato, R., de Oliveira, A., Menezes, G., Lelis, F., Avelar, R, Reis, H. Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity. Journal of psychiatric research 46, 738-742, (2012); Cosentino, M., Fietta, A. M., Ferrari, M., Rasini, E., Bombelli, R., Carcano, E., Lecchini, S. Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood 109, 632-642, (2007); Ferreira, T. B., Kasahara, T. M., Barros, P. O., Vieira, M. M., Bittencourt, V. C., Hygino, J. Bento, C. A. Dopamine up-regulates Th17 phenotype from individuals with generalized anxiety disorder. Journal of neuroimmunology 238, 58-66, (2011); Ilani, T., Strous, R. D. & Fuchs, S. Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 18, 1600-1602, (2004); Kipnis, J., Cardon, M., Avidan, H., Lewitus, G. M., Mordechay, S., Rolls, A., Schwartz, M. Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration. The Journal of neuroscience: the official journal of the Society for Neuroscience 24, 6133-6143, (2004)), the understanding of the central mechanisms, mediated by the dopaminergic network in the brain, is still limited.
Drugs, such as morphine and heroin, which act via dopamine neurons in the VTA, impose an immunosupressive effect (Devoino, L. V., Al'perina, E. L., Gevorgyan, M. M. & Cheido, M. A. Interaction between dopamine D1 and D2 receptors in modulation of the immune response. Bulletin of experimental biology and medicine 141, 553-555 (2006); Devoino, L. V., Al'perina, E. L., Gevorgyan, M. M. & Cheido, M. A. Involvement of dopamine D1 and D2 receptors in the rat nucleus accumbens in immunostimulation. Neuroscience and behavioral physiology 37, 147-151, (2007); Idova, G. V., Alperina, E. L. & Cheido, M. A. Contribution of brain dopamine, serotonin and opioid receptors in the mechanisms of neuroimmunomodulation: evidence from pharmacological analysis. International immunopharmacology 12, 618-625, (2012); Nistico, G., Caroleo, M. C., Arbitrio, M. & Pulvirenti, L. Evidence for an involvement of dopamine D1 receptors in the limbic system in the control of immune mechanisms. Neuroimmunomodulation 1, 174-180 (1994); Szczytkowski, J. L., Lebonville, C., Hutson, L., Fuchs, R. A. & Lysle, D. T. Heroin-induced conditioned immunomodulation requires expression of IL-1beta in the dorsal hippocampus. Brain Behav Immun 30, 95-102, (2013); Simonovska, N., Chibishev, A., Bozinovska, C., Grcevska, L., Dimitrovski, K. & Neceva, V. Evaluation of circulating immune complexes and antiphospholipid antibodies (anti beta 2 glycoprotein 1) in heroin addicts and their clinical significance. Medicinski arhiv 65, 324-326 (2011)), manifested, for example, by decreased NK cell activity, changes in lymphocyte proliferative responses, and nitric oxide production. Part of these effects are mediated via the central nervous system (CNS) as these immunoregulatory effects were shown to depend on the activation of dopamine receptors D(1) and D(2) in specific locations within the NAc (shell vs. core) (Assis, M. A., Valdomero, A., Garcia-Keller, C., Sotomayor, C. & Cancela, L. M. Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels. Brain Behav Immun 25, 647-657, (2011)).
Transcranial magnetic stimulation (TMS) uses electromagnetic induction to generate an electric current across the scalp and skull without physical contact. A plastic-enclosed coil of wire is held next to the skull and when activated, produces a magnetic field oriented orthogonal to the plane of the coil. The magnetic field passes unimpeded through the skin and skull, inducing an oppositely directed current in the brain that activates nearby nerve cells in much the same way as currents applied directly to the cortical surface (Cacioppo, J T; Tassinary, L G; Berntson, G G., ed. (2007). Handbook of psychophysiology (3rd ed.). New York, N.Y.: Cambridge Univ. Press. p. 121).